Breast Neoplasms
Conditions
Keywords
breast, neoplasms
Brief summary
To evaluate the preliminary activity and pharmacokinetics of 2 separate doses and schedules of orally administered Temsirolimus (CCI-779) given in combination with daily letrozole, compared to letrozole alone, in the treatment of locally advanced or metastatic breast cancer in postmenopausal women. All patients must be appropriate to receive endocrine therapy as treatment for advanced disease.
Interventions
DRUGLetrozole / Temsirolimus (CCI-779)
Letrozole 2.5 mg daily + Temsirolimus (CCI-779) 10 mg daily
DRUGLetrozole
Letrozole 2.5 mg daily
Sponsors
Pfizer
Wyeth is now a wholly owned subsidiary of Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Postmenopausal women with histologically confirmed, measurable locally advanced disease or metastatic breast. * Must be appropriate to receive endocrine therapy as treatment for advanced disease (chemotherapy; prior adjuvant therapy with antiestrogens other than aromatase inhibitors; prior adjuvant or first-line metastatic therapy with tamoxifen or trastuzumab, are permitted). * Women may either present with de novo advanced or metastatic cancer, or have had tumor progression while receiving adjuvant tamoxifen or at any time after completing adjuvant tamoxifen, or have had tumor progression while receiving first-line metastatic therapy with tamoxifen.
Exclusion criteria
* Patients having known central nervous system (CNS) metastases. * Prior therapy with Temsirolimus (CCI-779) or aromatase inhibitors. * Tamoxifen, or other hormonal therapy, in the metastatic or adjuvant setting within 1 week prior to day 1 of treatment on study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response (OR) | Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression | OR measured as Complete response (CR) or Partial response (PR) confirmed by assessments performed no less than 4 weeks after the criteria for the response are first met. CR=disappearance of all target and non-target lesions with normalization of tumor marker level; PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, referencing the screening sum LD. Target lesions=all measurable lesions up to 5 lesions per organ (10 lesions in total), representative of all involved organs, if possible; recorded and measured at screening. Non-target lesions=all other lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Disease Progression | Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression) | Number of days to disease progression defined as the interval from the date of randomization until the first date that recurrence or progression is documented; progression (at least 20% increase in the sum of the LD of target lesions taking as reference the smallest sum of LD; appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions). |
| Time to Treatment Failure | Baseline until Progressive disease, death, or discontinuation of study treatment | Number of days to treatment failure defined as interval from start of treatment to first date of progressive disease (at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD since the treatment started; appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions) or death or discontinuation of treatment due to Adverse Event, censored at last evaluation. |
| Percentage of Participants Exhibiting Freedom From Progression | Baseline, 8 weeks, 6 months, 12 months, and 24 months | Freedom from progression defined as CR (disappearance of all target and non-target lesions with normalization of tumor marker level), PR (at least a 30% decrease in sum of the LD of target lesions taking as reference the screening sum LD), or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD \[at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD since the treatment started; appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions\]). |
| Duration of Response | Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression) | Duration of response is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that reoccurrence or PD is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started. SD is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started; the minimal time interval for duration of SD is 8 weeks. |
| Number of Participants With Survival | Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) until death | Number of participants with survival (alive) in the interval from start of treatment to last contact for participant or death as a result of any cause. |
| Percentage of Participants With Best Overall Response (Clinical Benefit) | Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression) | Best response (CR, PR, or stable disease (SD) lasting ≥6 months) recorded from baseline to disease progression or recurrence (Progressive disease \[PD\]). CR=disappearance of all target and non-target lesions with normalization of tumor marker level; PR is ≥30% decrease in sum of LD of target lesions; SD=neither sufficient shrinkage to=PR nor sufficient increase to=PD, referencing smallest sum LD since treatment started; PD is ≥20% increase in sum of LD of target lesions referencing smallest sum of LD; appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. |
| Health Outcomes Assessment: European Organization for Research and Treatment of Cancer Quality of Life Questionaire (EORTC QLQ) BR23 | Prior to baseline, Cycle 7 (Week 12) and final visit (within 15 days of stopping study treatment) | Assess specificity of breast cancer symptoms relevant to participant's perceived quality of life (disease related symptoms of dry mouth, eye pain, hair loss, hot flushes, attractiveness, future health, sexual activity, arm or shoulder pain, breast pain, swollen breast, and skin problems on the breast). 23-item assessment of symptoms or problems during the past week (items 1-13 and 17-23) or during the past 4 weeks (items 14-16); range from 1 (not at all) to 4 (very much). Index scores transformed and range from 0 to 100; higher scores indicate higher level of functioning and quality of life. |
| Number of Participants With Antitumor Response in Relation to Expression of Akt Phosphorylation, Cyclin D1, PTEN, and p27 | Prior to baseline, after Cycle 4 (Week 8), after Cycle 8 (Week 14), and cross-over or final visit (within 15 days of stopping study treatment) | Number of participants with antitumor response (CR \[disappearance of all target and non-target lesions with normalization of tumor marker level\] or PR \[at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, referencing the screening sum LD\]) in relation to plasma levels of Akt phosphorylation, cyclin D1, PTEN, and p27. |
| Area Under the Concentration-time Curve (AUC) Sum | Cycle 1 Day 1 (1 cycle is defined as a 14 day duration) , Cycle 3 Day 1, and Cycle 4 Day 1, Day 6, Day 9, Day 11, and Day 12 | Area under the concentration-time curve to infinity (AUC) measured as hours multiplied by nanograms divided by milliliters (hr\*ng/mL) for CCI-779, sirolimus and letrozole. Sum is calculated as the sum of CCI-779 plus sirolimus AUCs (AUCsum). |
| 24-hour Trough Concentration (C Trough) | Cycle 1 Day 1 (1 cycle is defined as a 14 day duration) , Cycle 3 Day 1, and Cycle 4 Day 1, Day 6, Day 9, Day 11, and Day 12 | C trough in whole blood measured as nanograms per milliliter (ng/mL). |
| Health Outcomes Assessment: EuroQol (EQ-5D) Health State Profile Score | Prior to baseline, Cycle 7 (Week 12) and final visit (within 15 days of stopping study treatment) | EQ-5D is a self-administered questionnaire to assess health-related quality of life in 5 domains (mobility, self care, usual activities, pain or discomfort, and anxiety or depression). Scores from the 5 domains are used to calculate the Health State Profile Score as a single index value; range: 0.0 (death) to 1.0 (perfect health); higher scores indicate a better health state. |
Participant flow
Pre-assignment details
In the initial protocol, doses of CCI-779 were 25 mg daily and 75 mg intermittent; per protocol amendment, dosing was modified to 10 mg daily and 30 mg intermittent. All dose levels are included in the reporting groups.
Participants by arm
| Arm | Count |
|---|---|
| Let 2.5 mg Plus 10 mg Daily CCI-779 Letrozole (Let) 2.5 milligrams (mg) daily administered with a 10 mg daily dose of Temsirolimus (CCI-779). | 33 |
| Let 2.5 mg Plus 30 mg Intermittent CCI-779 Letrozole (Let) 2.5 mg administered daily with a 30 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). | 30 |
| Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 Letrozole (Let) 2.5 mg administered daily; permitted to cross-over at the time of progression to single-agent intermittent 75 mg dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). | 33 |
| Let 2.5 mg Plus 25mg Daily CCI-779 Letrozole (Let) 2.5 mg administered daily with a 25 mg daily dose of Temsirolimus (CCI-779). | 6 |
| Let 2.5 mg Plus 75 mg Intermittent CCI-779 Letrozole (Let) 2.5 mg administered daily with a 75 mg intermittent dose (daily for 5 days every 2 weeks) of Temsirolimus (CCI-779). | 6 |
| Total | 108 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 7 | 2 | 2 | 2 |
| Overall Study | Death | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Disease progression | 24 | 17 | 24 | 2 | 2 |
| Overall Study | Other | 2 | 3 | 1 | 0 | 1 |
| Overall Study | Symptomatic deterioration | 1 | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Let 2.5 mg Plus 25mg Daily CCI-779 | Let 2.5 mg Plus 10 mg Daily CCI-779 | Let 2.5 mg Plus 30 mg Intermittent CCI-779 | Let 2.5 mg Alone / Cross-over to 75 mg Intermittent CCI-779 | Let 2.5 mg Plus 75 mg Intermittent CCI-779 | Total |
|---|---|---|---|---|---|---|
| Age Continuous | 61.83 years STANDARD_DEVIATION 9.83 | 62.21 years STANDARD_DEVIATION 11.87 | 62.83 years STANDARD_DEVIATION 8.39 | 60.85 years STANDARD_DEVIATION 9.79 | 60.00 years STANDARD_DEVIATION 9.65 | 61.82 years STANDARD_DEVIATION 9.98 |
| Sex/Gender, Customized Female | 6 participants | 33 participants | 30 participants | 33 participants | 6 participants | 108 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 33 / 33 | 30 / 30 | 32 / 33 | 16 / 18 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 12 / 33 | 10 / 30 | 9 / 33 | 1 / 18 | 2 / 6 | 1 / 6 |
Outcome results
Primary
Percentage of Participants With Objective Response (OR)
OR measured as Complete response (CR) or Partial response (PR) confirmed by assessments performed no less than 4 weeks after the criteria for the response are first met. CR=disappearance of all target and non-target lesions with normalization of tumor marker level; PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, referencing the screening sum LD. Target lesions=all measurable lesions up to 5 lesions per organ (10 lesions in total), representative of all involved organs, if possible; recorded and measured at screening. Non-target lesions=all other lesions.
Time frame: Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression
Population: Intent to treat population (ITT) defined as all participants randomized in the study. Final efficacy analysis was not conducted because the development of temsirolimus (CCI-779) for the treatment of breast cancer was terminated.
Secondary
24-hour Trough Concentration (C Trough)
C trough in whole blood measured as nanograms per milliliter (ng/mL).
Time frame: Cycle 1 Day 1 (1 cycle is defined as a 14 day duration) , Cycle 3 Day 1, and Cycle 4 Day 1, Day 6, Day 9, Day 11, and Day 12
Population: ITT; Final analysis was not conducted.
Secondary
Area Under the Concentration-time Curve (AUC) Sum
Area under the concentration-time curve to infinity (AUC) measured as hours multiplied by nanograms divided by milliliters (hr\*ng/mL) for CCI-779, sirolimus and letrozole. Sum is calculated as the sum of CCI-779 plus sirolimus AUCs (AUCsum).
Time frame: Cycle 1 Day 1 (1 cycle is defined as a 14 day duration) , Cycle 3 Day 1, and Cycle 4 Day 1, Day 6, Day 9, Day 11, and Day 12
Population: ITT; Final analysis was not conducted.
Secondary
Duration of Response
Duration of response is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that reoccurrence or PD is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started. SD is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started; the minimal time interval for duration of SD is 8 weeks.
Time frame: Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression)
Population: ITT; Final efficacy analysis was not conducted.
Secondary
Health Outcomes Assessment: European Organization for Research and Treatment of Cancer Quality of Life Questionaire (EORTC QLQ) BR23
Assess specificity of breast cancer symptoms relevant to participant's perceived quality of life (disease related symptoms of dry mouth, eye pain, hair loss, hot flushes, attractiveness, future health, sexual activity, arm or shoulder pain, breast pain, swollen breast, and skin problems on the breast). 23-item assessment of symptoms or problems during the past week (items 1-13 and 17-23) or during the past 4 weeks (items 14-16); range from 1 (not at all) to 4 (very much). Index scores transformed and range from 0 to 100; higher scores indicate higher level of functioning and quality of life.
Time frame: Prior to baseline, Cycle 7 (Week 12) and final visit (within 15 days of stopping study treatment)
Population: ITT; Final efficacy analysis was not conducted.
Secondary
Health Outcomes Assessment: EuroQol (EQ-5D) Health State Profile Score
EQ-5D is a self-administered questionnaire to assess health-related quality of life in 5 domains (mobility, self care, usual activities, pain or discomfort, and anxiety or depression). Scores from the 5 domains are used to calculate the Health State Profile Score as a single index value; range: 0.0 (death) to 1.0 (perfect health); higher scores indicate a better health state.
Time frame: Prior to baseline, Cycle 7 (Week 12) and final visit (within 15 days of stopping study treatment)
Population: ITT; Final efficacy analysis was not conducted.
Secondary
Number of Participants With Antitumor Response in Relation to Expression of Akt Phosphorylation, Cyclin D1, PTEN, and p27
Number of participants with antitumor response (CR \[disappearance of all target and non-target lesions with normalization of tumor marker level\] or PR \[at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, referencing the screening sum LD\]) in relation to plasma levels of Akt phosphorylation, cyclin D1, PTEN, and p27.
Time frame: Prior to baseline, after Cycle 4 (Week 8), after Cycle 8 (Week 14), and cross-over or final visit (within 15 days of stopping study treatment)
Population: ITT; Final analysis was not conducted.
Secondary
Number of Participants With Survival
Number of participants with survival (alive) in the interval from start of treatment to last contact for participant or death as a result of any cause.
Time frame: Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) until death
Population: ITT; Final efficacy analysis was not conducted.
Secondary
Percentage of Participants Exhibiting Freedom From Progression
Freedom from progression defined as CR (disappearance of all target and non-target lesions with normalization of tumor marker level), PR (at least a 30% decrease in sum of the LD of target lesions taking as reference the screening sum LD), or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD \[at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD since the treatment started; appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions\]).
Time frame: Baseline, 8 weeks, 6 months, 12 months, and 24 months
Population: ITT; Final efficacy analysis was not conducted.
Secondary
Percentage of Participants With Best Overall Response (Clinical Benefit)
Best response (CR, PR, or stable disease (SD) lasting ≥6 months) recorded from baseline to disease progression or recurrence (Progressive disease \[PD\]). CR=disappearance of all target and non-target lesions with normalization of tumor marker level; PR is ≥30% decrease in sum of LD of target lesions; SD=neither sufficient shrinkage to=PR nor sufficient increase to=PD, referencing smallest sum LD since treatment started; PD is ≥20% increase in sum of LD of target lesions referencing smallest sum of LD; appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression)
Population: ITT; Final efficacy analysis was not conducted.
Secondary
Time to Disease Progression
Number of days to disease progression defined as the interval from the date of randomization until the first date that recurrence or progression is documented; progression (at least 20% increase in the sum of the LD of target lesions taking as reference the smallest sum of LD; appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions).
Time frame: Baseline, every 4 cycles (1 cycle is defined as a 14 day duration) up to Cycle 25, then every 6 cycles until disease progression)
Population: ITT; Final efficacy analysis was not conducted.
Secondary
Time to Treatment Failure
Number of days to treatment failure defined as interval from start of treatment to first date of progressive disease (at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD since the treatment started; appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions) or death or discontinuation of treatment due to Adverse Event, censored at last evaluation.
Time frame: Baseline until Progressive disease, death, or discontinuation of study treatment
Population: ITT; Final efficacy analysis was not conducted.